| Objective:The human immunodeficiency virus(HIV)has been considered a public health threat for human beings since its discovery.There are currently no effective vaccines against HIV-1,despite more than30 years of effort.Neither the immunity elicited with vaccines nor the immunity that develops during infection reliably controls rapidly mutating viruses such as HIV-1.Moreover,the ongoing mutation of HIV genes can eventuate in the selection of"escape variants"inured to host immunity.We invent and here propose the first critical test of a novel vaccine that we call the“mutable vaccine”.Methods:The mutable vaccine is a DNA construct designed to be optimally expressed and diversified in B cells.Upon stimulation of B cells,the vaccine appropriates mutation-inducing enzymes to diversify selected viral genes and elicits immunity to vaccine antigens and variants.We engineered mice to harbor the vector and tested the basic concept of"mutable vaccine"and its immunological efficacy.Results:The results showed that antigen env and its variants were expressed in the activated B cells of Env-mutator mice,the average mutation rate of env in germinal center B cells and plasma cells was65.2bp/10~4cells and 99.1bp/10~4cells,respectively.The amino acid sequence of env variants could be found in the naturally infected HIV database.In addition,the study demonstrated that some of the env variants are immunogenic,their affinity to major histocompatibility complex class I was stronger than that before the mutation,which evoked CD8+T cell immune response.Cells with“virus reservoirs”were eliminated in an effective immunological manner and the reduction could be reversed by inhibiting cellular immunity.Conclusion:We thus for the first time show that mutable vaccine,which can anticipate viral diversification,can evoke immunity to those variants and clear cell reservoirs to potentially thwart HIV infection or slow HIV evolution to exert control. |
